Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal diseases despite continual improvements in therapy. Thus new approaches are sorely needed. Mutations in the oncogenic KRAS gene occur in over 90% of PDACs. KRAS is a known regulator of glutamine metabolism that renders cancer cells dependent on glutamine. Therefore, targeting glutamine metabolism may be particularly effective in treating a large portion of patients with pancreatic cancer. The first step of glutamie metabolism is the conversion of glutamine to glutamate via glutaminase. We have demonstrated that small molecule glutaminase inhibitors, such as BPTES (bis-2-[5-(phenylacetamido)-1,3,4-thiadiazol-2-yl]ethyl sulfide), block the production of glutamine in pancreatic cancer cells and attenuate growth rates in both in vitro and in vivo preclinical models. However, BPTES and other available glutaminase inhibitors are generally poorly soluble, metabolically unstable, nonselective, and/or require high doses, which reduce their efficacy and therapeutic index. Recently, nano-sized vehicles to enhance drug delivery in cancer have been approved (e.g. Doxil(r), Abraxane(r)) and have been rationalized as an approach to circumvent the stromal barrier which is a clinical challenge to drug delivery in pancreatic cancer. We recently demonstrated that nanoparticle delivery of BPTES can be safely administered and relative to free BPTES, provides dramatic improvement in tumor drug exposure and retention, resulting in greater efficacy. We have now identified several proprietary BPTES derivatives that are 10- to 100-fold more potent than BPTES and, at the same time, retain the key physicochemical properties (cLogP, PSA) required for nanoparticle encapsulation and delivery. We plan to further optimize the potency of the glutaminase inhibitors (Aim 1) and their compatibility to encapsulation (Aim 2) and evaluate their effectiveness in orthotopic xenografts from KRAS mutated patient-derived pancreatic tumors as well as KrasLSL.G12D/+; p53R172H/+; PdxCretg/+ (or KPC) mice that develop natural pancreatic tumors with characteristic stroma (Aim 3). Ultimately, we seek to translate these findings into the clinic and improve outcomes for pancreatic cancer patients. The proposal builds on the complementary strengths of the three collaborating laboratories - Slusher (small molecule drug discovery), Hanes (nanoparticle design), and Le (cancer metabolism).